US3806535A

US3806535A - Cyclopentanol derivatives and process for the preparation thereof

Info

Publication number: US3806535A
Application number: US00310133A
Authority: US
Inventors: K Sakai; H Katano; K Kojima; T Yusa
Original assignee: Sankyo Co Ltd
Current assignee: Sankyo Co Ltd
Priority date: 1971-11-29
Filing date: 1972-11-28
Publication date: 1974-04-23
Anticipated expiration: 1991-04-23
Also published as: FR2162021A1; GB1384909A; FR2162021B1; CA966850A; CH567450A5; NL7216099A; BE792081A; DE2258516A1

Abstract

CYCLOPENTANOL DERIVATIVES HAVING THE FORMULA

2-(R-OOC-),3-(Y-A-),4-(HOOC-)CYCLOPENTANOL

WHEREIN A, Y AND R ARE THE SAME AS ABOVE.

2-(R-OOC-),3-(Y-A-),4-(HOOC-)CYCLOPENTANOL

WHEREIN A REPRESENTS A STRAIGHT OR BRANCHED ALYLENE GROUP HAVING 1-8 CARBON ATOMS, Y REPRESENTS CYANO GROUP, CARBAMOYL GROUP OR ANALKOXYCARBONYL GROUP HAVING 1-6 CARBON ATOMS IN THE ALKYL MOIETY AND R REPRESENTS AN ALKYL GROUP HAVING 1-6 CARBON ATOMS WHICH ARE USEFUL AS INTERMEDIATES FOR SYNTHESIS OF PROSTAGLANDIN FLA. THE CYCLOPENTANOL DERIVATIVE MAY BE PREPARED BY REDUCING A CYCLOPENTANONE DERIVATIVE HAVING THE FORMULA

Description

United States Patent 3,806,535 CYCLOPENTANOL DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF Kiyoshi Sakai, Koichi Kojima, Takashi Yusa, and Hamako Katano, Tokyo, Japan, assignors to Sankyo Company Limited, Tokyo, Japan No Drawing. Filed Nov. 28, 1972, Ser. No. 310,133 Claims priority, application Japan, Nov. 29, 1971, 46/96,037, 46/96,038 Int. Cl. C07c 61/36, 69/74 U.s.'cl. 260-468 K 4 Claims ABSTRACT OF THE DISCLOSURE Cyclopentanol derivatives having the formula (POOH wherein A represents a straight or branched alkylene group having 1-8 carbon atoms, Y represents cyano group, carbamoyl group or an alkoxycarbonyl group having 1-6 carbon atoms in the alkyl moiety and R represents an alkyl group having 1-6 carbon atoms which are useful as intermediates for synthesis of prostaglandin Fla.

The cyclopentanol derivative may be prepared by reducing a cyclopentanone derivative having the formula ooorr --A-Y Lo 0 0 R wherein A, Y and R are the same as above.

This invention relates to novel cyclopentanol derivatives and a process for the preparation thereof.

More particularly, it relates to cyclopentanol derivatives having the formula goon A Y Patented Apr. 23, 1974 ice oxycarbonyl and the group R may be methyl, ethyl, propyl, isopropyl, n butyl, pentyl and hexyl.

A preferred group of the compound provided by the present invention are those of the Formula I wherein A represents hexamethylene group and Y represents an alkoxycarbonyl group having 1-6 carbon atoms in the alkyl moiety, i.e., those having the formula coon ' bb-R GO,

OH lI- l wherein R is the same as above and R represents an alkyl group having 1-6 carbon atoms.

In the above Formulae I and I-a and elsewhere in this specification, a bond attached to the cyclopentane nucleus which is in the lat-configuration, i.e., extends below the plane of the cyclopentane ring, is represented by a dotted line, and a bond which is in the B-configuration, i.e., extends above the plane of the cyclopentane ring, is represented by a solid line.

The cyelopentanol derivatives having the above Formulae I and I-a are useful as intermediates used in the 2-formylcyclopentane derivatives having the formula manufacture of prostaglandin Flea having hypotensive and smooth muscle-stimulating activity.

It has 'been described in German patent Olfenlegungsschrift No. 2,044,698 that prostaglandin =F lot can be prepared from 2-formy1cyclopentane derivatives having the formula 320.. "p Uorro wherein A and Y are the same as above and R represents a tetrahydropyranyl group or an alkoxyalkyl group having 1-6 carbon atoms in each alkyl moiety and that the cyclopentane ring can be formed by oxidizing a bicyclopentane derivative prepared by a Diels-Alder reaction of cyclopentadiene with a diene com und. The 2-formylcyclopentane derivatives, however, cannot be stereo-specifically produced in the prior art, that is, the 2-formylcyclopentane derivatives are obtained as a mixture of a stereochemical isomer regarding to the substituents in the 1-, 2-, 3- and 4-position of the cyclopentane ring.

It is an object of the present invention to provide 2,4- dicarboxycyclopentanol derivatives having the substituents of the same configuration as prostaglandins, i.e., having the substituents of trans configuration in the 1-2 position, trans configuration in the 2-3 position and cis configuration in the 3-4 position and a process for the preparation thereof.

When the present process is employed as one of steps, there may be stereospecifically obtained prostaglandius.

According to the process of the present invention, the cyclopentanol derivative having the Formula I may 'be prepared by reducing a cyclopentanone derivative having the formula coon ' --AY UCOOB wherein A, Y and R are the same as above.

In the process of this invention, when the optical isomer or the racemic mixture of the compound having the Formula II are employed, there may be obtained the corresponding optical isomer or the racemic mixture of the compound having the Formula I.

The reduction may be preferably carried out by contacting the compound (Ill) with a metal hydride complex in the presence of a solvent or by subjecting the compound (II) to catalytic reduction.

As the metal hydride complex, there may be preferably employed an alkali metal hydride complex, for example, sodium boron hydride, potassium boron hydride and lithium boron hydride and an aluminum hydride complex, for example, aluminum trimethoxylithium hydride, aluminum tri-tert-butoxylithium hydride. It is desirable to employ an excess amount of the metal hydride complex. As the solvent, there may be employed any inert organic solvent without limitation that would not have an effect on the reaction.

Preferable examples of such a solvent include alcohols, e.g., methanol, ethanol, ethers, e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme; dialkylformamides, e.g., dimethylformamide.

The reaction temperature is not critical, but it is preferable to carry out the reaction at low temperatures in order to control side reactions, preferably at the temperature ranging from 'l0 C. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the metal hydride complex and may vary from about 5 minutes to one hour. When the reaction is carried out by catalytic reduction, there may be preferably employed, as the catalyst, platinum catalyst, e.g., platinum wire, platinum plate, platinum black, spongy platinum, platinum oxide, colloidal platinum. The reaction is usually carried out in the presence of a solvent. As the solvent, there may be employed any solvent without limita tion that would not have an effect on the reaction.

Preferable examples of such a solvent include water; alcohols, e.g., methanol, ethanol, ethylene glycol; ethers, e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme; hydrocarbons, e.g., benzene, toluene, cyclohexane, methylcyclohexane; esters, e.g., ethyl acetate; carboxylic acids, e.g., acetic acid; and dialkylformamides, e.g., dimethylformamide. The reaction may be carried out under ordinary pressure or increasing pressure. The reaction tempeature is not critical but the reaction is preferably carried out at low temperature in order to control side reactions, preferably at room temperature. The reaction ends when the absorption of hydrogen gas ceases.

After completion of the reaction, the desired product may be recovered from the reaction mixture by conventional means. For instance, when the metal hydride is employed, organic acids such as formic acid and acetic acid are added to the reaction mixture in order to decompose the reducing agent and the mixture is made acidic. The mixture is extracted with an organic solvent and the extract is washed with water and dried. The solvent is distilled off to give the desired product. When the reduction is carried out by catalytic reduction, the reaction mixture is filtered to remove the catalyst employed and the solvent is distilled off from the filtrate to give the desired product. The desired product thus obtained may be, if necessary, further purified by conventional means, for example, column chromatography or thin-layer chromatography.

On the present reaction there m y be st sp fi l y obtained the cyclophentanol derivative (I) having the substituents of trans configuration in the 1-2 position, trans configuration in the 2-3 position and cis configuration in the 3-4 position.

The compounds having the above Formula II, employed as starting materials, are novel and can be prepared by the process shown in the following reaction schema.

CHzCO CHzC O OCHzPh (III) In the above formulae, A, Y and R are the same as above and R represents an alkyl group having 1-6 carbon atoms, Ph represents phenyl group, Hal represents a halogen atom such as chlorine and bromine and the formula represents the formula or a mixture thereof.

Each of the above steps will be illustrated as follows:

The compound (V) may be prepared by contacting the compound (III) with the compound (IV) in the presence of a base.

Examples of the base include in alkali metals e.g. metallic sodium; metal hydrides e.g. sodium hydride; and thallium compounds, e.g., thallium hydroxide, methoxythallium. The reaction is usually carried out in the presence of a solvent. As the solvent, there may be employed any solvent without limitation that would not have an effect on the reaction.

Examples of such a solvent include hydrocarbons, e.g. benzene, toluene and ethers, e.g., diethyl ether, tetrahydrofuran, dioxane. These solvents are preferably employed especially in anhydrous condition. The reaction temperature is not critical, but it is preferably from --10 C. to 40 C. The reaction period will depend mainly upon the reaction temperature and a kind of the base employed and may vary from 30 minutes to 15 hours.

The compound (VII) or the compound (VIII) or a mixture thereof may be prepared by contacting the compound (V) with the compound (VI) in the presence of a base. As the base, there may be preferably employed a strong base such as alkali metals, e.g., metallic sodium; alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide; alkali metal hydrides, e.g., sodium hydride; alkali metal alkoxide, e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium ethoxide; alkali metal amides, e.g., sodium amide, potassium amide; and metal salts of dialkyl sulfoxide, e.g., sodiumor potassium salt of dimethyl sulfoxide. The reaction is usually carried out in the presence of a solvent. As the solvent, there may be employed any inert organic solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include hydrocarbons, e.g., benzene, toluene, cyclohexane; ethers, e.g., diethyl ether, dimethoxy ethane, dioxane, tetrahydrofuran; dialkylformamide, e.g., dimethylformamide; and dialkyl sulfoxide, e.g., dimethyl sulfoxide. The reaction temperature is not critical and it is usually from at room temperature to a reflux temperature of a solvent employed; The reaction period will depend mainly upon the reaction temperature and a kind of the base and may vary from about 2 hours to 24 hours.

The compound (IX) may be prepared by contacting the compound (VII) or the compound (VIII) or a mixture thereof with an acid. As the acid, there may be preferably employed an organic strong acid such as trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, benzenesulfonic acid and p-toluene-sulfonic acid and a mineral acid such as hydrochloric acid, perchloric acid, sulfuric acid and phosphoric acid. The reaction may be carried out in the presence or absence of a solvent, but it is preferable to employ Ia solvent in order to proceed the reaction smoothly. As the solvent, there may be any solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include hydrocarbons, e.g., benzene, toluene, cyclohexane; ethers, e.g., diethyl ether, dimetho-xy ethane, dioxane, tetrahydrofuran; dialkylformamides, eg., dimethylformamide; dialkyl sulfoxides, e.g., dimethyl sulfoxide; hydrocarbon halide, e.g., dichloromethane, trichloromethane, carbon tetrachloride aud esters, e.g., ethyl acetate. The reaction temperature is not critical, but it is usually from C. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the acid and may vary usually from 1 hour to 10 hours.

The compound (X) may be prepared by contacting the compound (IX) with a base. Examples of the base include alkalior alkaline earth metal hydroxides, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide; alkalior alkaline earth metals, e.g., metallic sodium, -potassium, -calcium, -barium; alkali metal carbonates, e.g., sodium carbonate, potassium carbonate; alkali metal bicarbonates, e.g., sodium bicarbonate, potassium bicarbonate, alkalior alkaline earth metal acetates, e.g., sodium acetate, potassium acetate, calcium acetate; alkalior alkaline earth metal alkoxides, e.g., sodium methoxide, potassium ethoxide, calcium ethoxide; and alkali metal fluorides, e.g., sodium fluoride, potassium fluoride. The reaction is usually carried out in the presence of a solvent. As the solvent, there may be employed without limitation that would not have an effect on the reaction. Examples of such a solvent include ethers, e.g., diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran; hydrocarbons, e.g., benzene, toluene, cyclohexane; and alcohols, e.g., methanol, ethanol, ethylene glycol. The reaction temperature is not critical, but the reaction may be preferably carried out at the temperature ranging from -10 C. to 50 C. The reaction period will depend mainly upon the reaction temperature and a kind of the base employed and may vary from about 30 minutes to 10 hours.

Alternatively, the compound (X) may be prepared by contacting the compound (V) with the compound (XI) in the presence of a strong base. Examples of the base include alkali metals, e.g., metallic sodium, alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide;

alkali metal hydrides, e.g., sodium hydride; alkali metal alkoxide, e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium ethoxide; alkali metal amides, e.g., sodium amide, potassium amide; and alkali metal salts of dialkyl sulfoxide, e.g., sodiumor potassium salt of dimethyl sulfoxide. The reaction is preferably carried out in the presence of a solvent. As the solvent, there may be employel any inert organic solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include hydrocarbons, e.g., benzene, toluene cyclohexane; ethers, e.g., diethyl ether, dimethoxymethane, dioxane, tetrahydrofuran; dialkylformamides, e.g., dimethylformamide; and dial'kyl sulfoxide, e.g., dimethyl sulfoxide. The reaction temperature is not critical, but the reaction may be preferably carried out at the temperature ranging from 0 C. to 50 C. The reaction period will depend mainly upon the reaction temperature and a kind of the base employed and may vary from one hour to 10 hours.

The compound (II) may be prepared by subjecting the compound (X) to catalytic reduction in the presence of a solvent. As the catalyst which may be used in the reaction, there may be preferably employed palladium catalyst such as palladium black, palladium oxide, colloidal palladium, anhydrous colloidal palladium, palladium-barium sulfate, palladium on charcoal, palladium on bariumor strontium carbonate and palladium on silica gel; rhodium catalyst such as rhodium asbestos and colloidal rhodium; iridium catalyst such as iridium asbestos and colloidal iridium; nickel catalyst such as reduced nickel catalyst, nickel oxide catalyst, Raney nickel catalyst, Urushibara nickel catalyst and nickel boride catalyst; cobalt catalyst such as Raney cobalt catalyst, reduced cobalt catalyst and Urushibara cobalt catalyst; iron catalyst such as reduced iron catalyst and Raney iron catalyst; copper catalyst such as reduced copper catalyst, copper on carrier and Raney copper catalyst. As the solvent, there may be employed any solvent without limitation that would not have an effect on the reaction. Preferable examples of such a solvent include water; alcohols, e.g., methanol, ethanol and ethylene glycol; ethers, e.g., diethyl ether, dioxane and tetrahydrofuran; hydrocarbons, e.g., benzene, toluene, cyclohexane and methylcyclohexane; esters, e.g., ethyl acetate; and carboxylic acids, e.g. acetic acid. The reaction may be carried out under ordinary pressure or increasing pressure. The reaction temperature is not critical, but the reaction is preferably carried out at from 0 C. to room temperature. The reaction ends when the absorption of hydrogen gas ceases. On the present reaction, there may be stereospecifically obtained the cyclopentanone derivatives (II) having substituents of trans configuration in the 2-3 position and cis configuration in the 3-4 position.

The known 2-formylcyclopentane derivatives (U) can be prepared from the cyclopentanol derivatives (I) by the process shown in the following reaction schema.

c 0 on go on c OHal Y ..A Y

0 0 OR GO OR K) on on B (1) (XII) (XIII) QH QC OR 30R --AY CODE. 0 0 OR GO OR (XVI) (XV) (XIV) 9 9 z I ...A.

COOR CH OH om om 0R (XVII) (XIX) (XX) --'A-COOH U0 0 OR (XVIII) In the above formulae, A, Y, R, R and Hal are the same as above, R represents an acyl group of a hydrocarbon carboxylic acid containing 1-12 carbon atoms, R represents an alkyl group having l-6 carbon atoms and Z represents Y or carboxyl group.

Each of the above steps will be illustrated as follows:

The compound (XII) may be prepared by contacting the compound (II) with a hydrocarbon carboxylic acid or a halide or anhydride thereof. The reaction may be carried out in the presence or absence of a solvent. Examples of the carboxylic acid or the halide or anhydride include acetic acid, propionic acid, benzoic acid, the chloride, bromide 0r anhydride of such an acid. Preferable examples of a solvent include amines, e.g., pyridine, triethylamine; halogenohydrocarbons, e.g., chloroform, dichloromethane; ethers, e.g., diethyl ether, tetrahydrofuran, dioxane; hydrocarbons, e.g., benzene, toluene; ethers, e.g., ethyl acetate. The reaction temperature is not critical, but preferably the reaction may be carried out at the temperature ranging from 0 C. to room temperature. The reaction period depends mainly upon the reaction temperature and a kind of the reagent and may vary from about one hour to 24 hours.

The compound (XIII) may be prepared by contacting the compound (XII) with a halogenating agent. As the halogenating agent, there may be employed dicarboxylic halides, e.g., oxalyl chloride, oxalyl bromide, malsyl chloride, succinyl chloride; phosphorus halides, e.g., phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide; thionyl halides, e.g., thionyl chloride, thionyl bromide; a mixture of triarylphosphine and carbon tetrahalide, e.g., a mixture of triphenylphosphin and carbon tetrachloride. As a solvent, there may be preferably employed an inert organic solvent such as ethers, e.g., diethyl ether, dioxane, tetrahydrofuran; hydrocarbons, e.g., benzene, toluene. The reaction temperature is not critical and usually the range of the reaction may be carried out at the temperature ranging from 0 C. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the halogenating agent and may vary from about minutes to 5 hours.

The compound (XIV) may be prepared bycontacting the compound (XIII) with an alkylating agent. As the alkylating agent, there may be employed alkyl metal compounds such as dialkylcopperlithium, e.g., dimethylcopperlithium, diethylcopperlithium; a dialkylcadmium, e.g., dimethylcadmium, diethylcadmium; an alkyllithium, e.g., ethyllithium; a Grignard reagent, e.g., methylmagnesium bromide, ethylmagnesium iodide. The reaction is carried out in the presence of a solvent. As the solvent, there may be employed any inert organic solvent without limitation that would not have an effect on the reaction. Preferable examples of such a solvent include ethers, e.g., diethyl ether, dimethoxyethane dioxane, tetrahydrofuran; hydrocarbons, e.g., benzene, toluene. The reaction temperature is not critical. In case of employing the dialkylcopperlithium, the alkyllithium or the Grignard reagent, the reaction is desirably carried out at relatively low temperature, preferably at the temperature ranging from C. to room temperature, in order to control side reactions. The reaction period will depend mainly upon the reaction temperature and a kind of the alkylating agent and may vary from about 5 minutes to 10 hours.

In case of employing the dialkylcadmium as the reagent, the reaction is carried out at relatively high temperatures, usually at the temperature ranging from room temperature to a reflux temperature of a solvent employed. The reaction period will depend mainly upon the reaction temperature and may vary from about 30 minutes to 5 hours.

The compound (XV) may be prepared by contacting the compound (XVI) with peroxides. As the peroxides, there may be preferably employed organic peroxides, for example, performic acid, peracetic acid, perpropionic acid, perluric acid, percomphoric acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid and monoperphthalic acid and hydrogen peroxide. The reaction may be carried out in the presence or absence of a solvent. It is preferable to employ a solvent in order to proceed the reaction smoothly. As a solvent, there may be employed any solvent without limitation that would not have an effect on the reaction. Preferable examples of such a solvent include halogenohydrocarbons, e.g., chloroform, dichloromethane; ethers, e.g., dioxane, tetrahydrofuran; esters, e.g., ethyl acetate. The reaction temperature is not critical, but the reaction is desirably carried out at low temperatures, preferably at the temperature ranging from -l0 C. to room temperature, in order to control side reactions. The reaction period will depend mainly upon the reaction temperature and a kind of the peroxides and may vary from about 10 minutes to 10 hours.

The compound (XVI) may be prepared by contacting the compound (XV) with a base. As the base, there may be employed alkalior alkaline earth hydroxides, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide; alkali metal carbonates, e.g., sodium carbonate, potassium carbonate; alkali metal bicarbonate, e.g., sodium bicarbonate, potassium bicarbonate; alkalior alkaline earth metal alkoxides, e.g., sodium methoxide, potassium ethoxide, calcium ethoxide; organic amines, e.g., trimethylamine, triethylamine, pyridine, piperidine.

The reaction is preferably carried out in the presence of a solvent. As the solvent, there may be employed water; alcohols, e.g., methanol, ethanol; ethers, e.g., dioxane, tetrahydrofuran; dialkylformamides, e.g., dimethylformamide; dialkyl sulfoxides, e.g., dimethyl sulfoxide; and a mixture of water and such an organic solvent. The reaction temperature is not critical, but the reaction may be preferably carried out at the temperature ranging from room temperature to 70 C. The reaction period will depend mainly upon the reaction temperature and a kind of the base employed and may vary from about 30 minutes to 3 hours.

The compound (XVII) may be prepared by contacting the compound (XVI) with tetrahydropyran or alkoxyalkyl halides. When the tetrahydropyrans are employed as a reactant, the reaction is carried out in the presence of a small amount of acids.

Examples of the tetrahydropyrans include tetrahydropyran, tetrahydrothiopyran, 4-methoxytetrahydropyran. As the acids, there may be employed a mineral acid, for example, acid, e.g., hydrochloric acid, hydrobromic acid and an organic acid, for example, picric acid, trifiuoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid. The reaction may be carried out in the presence or absence of a solvent. It is preferable to employ a solvent in order to proceed the reaction smoothly. As the solvent, there may be employed any inert Organic solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include halogenohydrocarbons, e.g., chloroform, dichloromethane and nitriles, e.g., acetonitrite.

When the alkoxyalkyl halides are employed as a reactant, the reaction is carried out in the presence of a base. As the base, there may be employed alkali metal hydrides, e.g., sodium hydride, potassium hydride, lithium hydride, alkali metal amides, e.g., sodium amide, potassium amide, alkali metal alkoxides, e.g., sodium methoxide, potassium ethoxide and dialkylsulfoxide metal salt, e.g., dimethylsulfoxide sodium salt, dimethylsulfoxide potassium salt.

The reaction may be carried out in the presence or absence of a solvent. It is preferable to employ a solvent in order to proceed the reaction smoothly. As the solvent, there may be employed any inert organic solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include ethers, e.g., tetrahydrofuran, dioxane, diethyl ether; hydrocarbons, e.g., benzene, toluene, cyclohexane; dialkylf'ormamide, e.g., dimethylformamide; and dialkylsulfoxide, e.g., dimethyl sulfoxide. The reaction temperature is not critical, but the reaction may be preferably carried out at the temperature ranging from C. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the reactant and may vary from about one hour to 24 hours.

The compound (XVIII) may be prepared by contacting the compound (XVII) with a base. As the base, there may be preferably employed alkalior alkaline earth hydroxides, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide; alkali metal carbonates, e.g., sodium carbonate potassium carbonate; alkali metal bicarbonate; e.g., sodium bicarbonate potassium bicarbonate; alkalior alkaline earth metal alkoxides, e.g., sodium methoxide, potassium ethoxide, calcium ethoxide. The reaction is preferably carried out in the presence of a solvent. As the solvent, there may be employed water, alcohols, e.g.,

methanol, ethanol; ethers, e.g., dioxane, tetrahydrofuran;

dialkylformamides, e.g., dimethylformamide; dialkyl sulfoxides e.g., dimethyl sulfoxide; and a mixture of water and such an organic solvent. The reaction temperature is not critical, but the reaction may be preferably carried out at the temperature ranging from room temperature to reflux temperature of the solvent. The reaction period will depend mainly upon the reaction temperature and a kind of the base employed and may vary from about 30 minutes to 10 hours.

The compound (XIX) may be prepared by reducing the compound (XVII) or (XVIII) with a reducing agent. As the reducing agent, there may be employed a metal hydride complex, for example, sodium boron hydride, potassium boron hydride, lithium boron hydride, lithium aluminum hydride and tri-tert-butoxy lithium aluminum. The reaction is preferably carried out in the presence of a solvent. As the solvent, there may be employed any inert organic solvent without limitation that would not have an effect on the reaction. Examples of such a solvent include alcohols, e.g., methanol, ethanol; ethers, e.g., tetrahydrofuran, dioxane. The reaction temperature is not critical, but the reaction is preferably carried out at the temperature ranging from 0 C. to reflux temperature of a solvent employed. The reaction period will depend mainly upon the reaction temperature and a kind of the reductan't and may vary from about hours to hours.

The compound (XX) may be prepared by contacting the compound (XIX) with an oxidizing agent in the presence of a solvent. As the oxidizing agent, there may be preferably employed chromic compounds, e.g., chromic acid, chromic anhydride, chromic acid-pyridine complex, sodium bichromate, potassium bichromate; halogenoamides, e.g., N-bromoacetamide, N-chlorobenzenesulfonamide; halogenoimides, e.g., N-bromosuccinirnide, N-bromophthalimide; aluminum alkoxides, e.g., aluminum tertbutoxide, aluminum isopropoxide; dimethyl sulfoxide-dicyclohexylcarbodiimide; and dimethyl sulfoxidc-acetic anhydride. As the solvent, there may be employed any solvent without limitation that would not have an effect on the reaction, but a preferable solvent is different depending upon the oxidizing agent. When chromic acids are employed, there may be preferably employed carboxylic acids, e.g., acetic acid, a mixture of a carboxylic acid and a carboxylic acid anhydride, e.g., acetic acid-acetic anhydride; halogenohydrocarbon, e.g., methylene chloride, chloroform and carbon tetrachloride. When organic active halides are employed, there may be preferably employed an aqueous organic solvent, for example, aqueous tertbutanol, aqueous acetone and aqueous pyridine. When aluminum alkoxides are employed, there may be preferably employed aromatic hydrocarbons, for example, benzene, toluene and xylene. In this case, it is preferable to employ, as a hydrogen acceptor, an excess amount of ketones, for example, acetone, methyl ethyl ketone, cyclohexanone and it is necessary to remove water completely from the reaction system. When dimethyl sulfoxide-dicyclohexylcarbodiimide or dimethyl sulfoxide-acetic anhydride is employed, there may be preferably employed an excess amount of the dimethyl sulfoxide without employment of other solvents. When dimethyl sulfoxide-dicyclocarbodiimide is employed, there is employed, as usual, a catalytic amount of acids, e.g., phosphoric acid, acetic acid, trifluoroacetic acid. As the oxidizing agent, there may be most preferably employed chromic acids, especially chromic acid-pyridine complex. The reaction temperature is not critical, but it is desirable to carry out the reaction at low temperatures in order to control side reactions. It is preferably from 30 C. to room temperature, most preferably from 0 C. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the oxidizing agent and may vary from several minutes to one hour.

In the process mentioned above the compound (II) can be produced as racemic mixtures and the racemic mixtures can be resolved at appropriate stages by methods well known in the art, whereupon subsequent products may be obtained as the corresponding optically pure isomers. In the above schema both the optical isomer and the racemic forms are depicted by a single representation. But it should not be considered to limit the scope of the disclosure. Prostaglandin F10: [9a, 15a-trihydroxyprost-13 (trans)-enoic acid] can be prepared from the 2-formylcyclopentane derivative (XX) by a known method. For instance, it can be prepared by reacting the compound (XX) with a Wittig reagent, e.g., tri-n-butylphosphin-2-oxoheptylide, reducing the product with an alkali metal boron hydride, e.g., sodium boron hydride and next hydrolyzing the product with an acid, e.g., acetic acid and, if necessary, subsequently with an alkali, e.g., potassium hydroxide.

On each step mentioned above, the reaction product may be recovered from the reaction mixture and purified by conventional means, for example, column chromatography and thin-layer chromatography. The following preparations and example are given for the purpose of illustration of this invention.

PREPARATION 1 Benzyl 3-oxo-9-ethoxycarbonylnonanoate (V) To 250 ml. of anhydrous ether is added 3.76 g. of granulated metallic sodium and to the mixture is added dropwise 32 g. of benzyl acetoacetate under ice-cooling and stirring over one hour. After completion of the addition, the mixture is further stirred at room temperature for 4 hours. To the mixture is added dropwise 31 g. of l-ethoxycarbonylheptanoyl chloride little by little under ice-cooling. After completion of the addition, the mixture is stirred at room temperature for 12 hours and subsequently refluxed for 30 minutes. After completion of the reaction, ice water is added to the reaction mixture under ice-cooling. The ether layer is separated, washed successively with 5% sulfuric acid and water and dried over anhydrous sodium sulfate. The ether is distilled off from the ether solution to give oils. The oils are again dissolved in 450 ml. of anhydrous ether and into the solution is passed ammonia gas for 30 minutes under ice-cooling and subsequently for 2 hours at room temperature. Argon gas is passed into the reaction mixture in order to put out the ammonia gas dissolved in the reaction mixture. The ether layer is washed successively with a 3 N hydrochloric acid solution and water and dried over anhydrous sodium sulfate. The ether is distilled off from the ether solution. The oily residues are subjected to vacuum distillation and the fraction distilled at 180 C. (oil bath temperature) 10.1- 0.2 mm. Hg are removed. The oily residues are subjected to chromatography using neutral alumina (Grade III, Woelm Co.) and eluted successively with some amount of hexane-a hexane solution containing 10% benzene and next successively with a hexane solution containing 20- 40% benzene. The eluates with the hexane solution containing 20-40% benzene are collected and the solvent is distilled off to give 13.3 g. of the oily desired product.

LR. (liquid film) v cmr z N.M.R. (CD01 r:p.p.m.

2.61 (5H, singlet, C -H 4.80 (2H, singlet,

5.83 (2H, quartette, 'CH CH OCO) 6.51 (2H, singlet,

Q-omo c 01120 0-) 8.75 (3H, triplet, CH CH OCO) PREPARATION 2 2-methoxy-2-methoxycarbonylmethyl 4 benzyloxycarbonyl-S-(6-ethoxycarbonylhexyl) 2,3 dihydrofuran (VII) and methyl 3-methoxy-S-benzyloxycarbonyl-6- oxo-12-ethoxycarbonyldodeca-Z-enoate (VHI) To 100 ml. of dry benzene are added 16.166 g. of benzyl 3-oxo-9-ethoxycarbonylnonanoate and 1.1 g. of granulated metallic sodium and the mixture is stirred at room temperature overnight. To the mixture is added 9 g. of methyl-4-bromo-3-methoxy-2-butenoate and the mixture is refluxed for 4.25 hours. After completion of the reaction, the reaction mixture is cooled and Washed successively with a dilute sulfuric acid solution and Water and dried over anhydrous sodium sulfate. The solvent is distilled OE and the residues are subjected to column chromatography using 200 g. of neutral alumina (Grade III, Woelm Co.) and eluted successively with some amount of hexane-a hexane solution containing 8% benzene and next with a hexane solution containing 10% benzene. The eluates with the hexane solution containing 10% benzene are collected and the solvent is distilled ofl? to give 1.548 g. of 2-methoxy-2-methoxycarbonylmethyl-4- benzyloxycarbonyl--(6 ethoxycarbonylhexyl)-2,3-dihydrofuran as oil. The elution with a hexane solution containing benzene is further continued to give 1.623 g. of a mixture of 2-methoxy-2-methoxycarbonylmethyl-4- benzyloxycarbonyl-S-(6-ethoxycarbonylhexyl) 2,3 dihydrofuran and methyl 3-methoxy-5-benzyloxycarbonyl- 6-oxo-l2-ethoxycarbonyldodeca-2-enoate as oil. Furthermore the elution with a hexane solution containing l0 20% benzene is continued to give 6.975 g. of methyl 3- methoxy-S-benzyloxycarbonyl 6 oxo 12 ethoxycarbonyldodeca-Z-enoate as oil.

12 2-methoxy-2-methoxycarbonylmethyl 4 benzyloxycarbonyl-5-(6-ethoxycarbonylhexyl)-2,3-dihydrofuran.

I.R. (liquid film) v cmr z 1645, 1700, 1738. N.M.R. (CDCI 'r:p.p.m.

2.64 (5 H, singlet, CH 4.83 (2H, singlet, C H CH OCO-) 5.88 (2H, quartette, CH CH OCO) 6.32 3H, singlet, CH OCO-) 6.70 (3H, singlet, CH O-) 8.76 (3H, triplet, OH CH 0CO-) Methyl 3-methoxy-5-benzyloxycarbonyl-6-oxo-12- ethoxycarbonyldodeca-Z-enoate 1R. (liquid film) v cm- 1630, 1712, 1741. N.M.R. (CD013) 1-:p.p.m.

2.67 (5H, singlet, C H 4.82 (2H, singlet, C H CH OOO) 4.95 (1H, singlet,

CHaOCOC=CCHz-) H CH;

6.33 (3H, singlet, CH OCO-) 6.50 (3H, singlet, CH 0 PREPARATION 3 Methyl 3,6-dioxo-S-benzyloxycarbonyl-12-ethoxycarbonyldodecanoate (IX) In 5 m1. of chloroform is dissolved mg. of methyl 3 methoxy-S-benzyloxycarbonyl-6-oxo-l2-ethoxycarbonyldodeca-Z-enoate and to the solution is added 15 drops of trifluoroacetic acid and the solution is stirred at room temperature for 2 hours. After completion of the reaction, water is added to the reaction mixture. The mixture is extracted with ether. The ether layer is separated, washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 105 mg. of the desired product as oil.

I.R. (liquid film) v cmr z N.M.R. (CDCI 'r:p.p.m.

2.67 (5H, singlet, C H e-) 4.85 (2H, singlet, C H CH OCO-) 5.89 (2H, quartette, CH CH OCO-) 6.30 (3H, singlet, CH 0CO) 8.78 (3H, triplet, CH CH OCO) PREPARATION 4 Methyl 3 ,6-dioxo-5-benzyloxycarbonyl-12-ethoxycarbonyldodecanoate (IX) 2-methoxycarbonyl-3-(6-ethoxycarbonylhexyl)-4-benzyloxycarbonylcyclopentenone (X) In 20 ml. of absolute methanol is dissolved 505 mg. of methyl 3,6-dioxo-S-benzyloxycarbonyl 12 ethoxycarbonyldodecanoate and to the solution is added 400 mg. of potassium bicarbonate. The mixture is stirred at room temperature for 2 hours under heating at intervals. After completion of the reaction, the reaction mixture is diluted with water and made alkaline by addition of acetic acid and extracted with ether. The extract is washed with wais distilled off from the extract. The residues are subjected to column chromatography using g. of silica gel and eluted with some amount of benzene and next successively with benzene-a benzene solution containing 1% ether. The eluates with benzene-a benzene solution containing 1% ether are collected and the solvent is distilled olf to give 280 mg. of the desired product as oil.

I.R. (liquid film) v cmr z 700, 750, 1630, 1735, 3300-3500. N.M.R. (CDCl 1-:p.p.m.

@omoo o- 5.87 (2H, CH CH OCO'-) 6.16 (3H, CH OCO) 8.75 (3H, CH CH OCO) PREPARATION 6 2-methoxycarbonyl-3-(6-ethoxycarbonylhexyl)-4 benzyloxycarbonylcyclopentenone (X) To a mixture of 0.34 g. of granulated metallic sodium and 20 m1. of 1,2-dimethoxyethane is added dropwise 5 g. of benzyl 3-oxo9-ethoxycarbonylnonanoate at room temperature. After the metallic sodium is disssolved, 1.4 g. of methyl -bromoacetoacetate in ml. of 1,2-dimethoxyethane is added dropwise to the solution. The mixture is stirred at room temperature for 3 hours. After completion of the reaction, 100 ml. of ice water is added to the reaction mixture. The mixture is extracted with hexaneether (1:1) to remove the unreacted starting material. To the aqueous layer is added 10% hydrochloric acid under ice-cooling to adjust to pH 3 and the aqueous layer is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled olf to give 2.161 g. of the desired product as oil.

The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product are the same as those of the product obtained in Preparation 5.

PREPARATION 7 2 fi-methoxycarbonyl-3 a- (6 -ethoxycarb onylhexyl) 4ctcarboxylcyclopentanone (II) In 40 ml. of methanol is dissolved 249 mg. of 2-methoxycarbonyl-3-(6 ethoxycarbonylhexyl) 4 benzyloxycarbonylcyclopentenone and to the solution is added 300 mg. of 5% palladium on charcoal. The mixture is subjected to catalytic reduction. The reduction is completed when approximately 25 ml. of hydrogen gas is absorbed. After completion of the reaction, the catalyst is removed from the reaction mixture and the solvent is distilled off. The residues are subjected to column chromatography using 4 g. of silica gel washed with an acid and eluted successively with some amount of benzenea benzene solution containing 2% ether and next with a benzene solution containing 5% ether. The eluates with the benzene solution containing 5% ether are collected and the solvent is distilled off to give 127 mg. of the desired product as oil.

LR. (liquid film) v cmf t 1700, 1740, 1750, 3200 (broad). N.M.R. (CDCl T: .m.

2.06 (1H, singlet, COOH) 5.88 (2H, quartette, CH CH OCO) 6.23 (3H, singlet, CH OCO) 8.74 (3H, triplet, CH CH OCO-) 14 PREPARATION s 1a-acetoxy-2,8-methoxycarbonyl-3 u-(6-ethoxycarbonylhexyl)4a-carboxycyclopentane (XII) In 4 ml. of pyridine is dissolved 652 mg. of lwhydroxy- 2fl-methoxycarbonyl-3a-(6 ethoxycarbonylhexyl) 4acarboxycyclopentane and to the solution is added 2 ml. of anhydrous acetic acid. The mixture is left to stand for 10 hours at 0 C. and subsequently for 3 hours at room temperature after addition of water. The reaction mixture is diluted with water, made acidic by addition of dilute hydrochloric acid and extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled 0E. The residues are subjected to column chromatography using 7 g. of silica gel and eluted with some amount of benzene and next successively with a benzene solution containing 15% ether. The eluates 'with the benzene solution containing 15% ether are collected and the solvent is distilled oil. to give 590 mg. of the desired product as oil.

1720, 1750, 3250 (broad). N.M.R. (CDCl -r:p.p.m.

1.48 (1H, broad singlet, COOH) 4.71 (1H, multiplet,

5.85 (2H, quartette, CH CH OCO-) 6.27 (3H, singlet, CH OCO) 7.95 (3H, singlet, CH COO-) 8.73 (3H, triplet, CH CH OCO) PREPARATION 9 1a-acetOXy-ZB-methoxycarbonyl-3t:- 6-ethoxycarbonylhexyl)-4a-chlorocarbonylcyclopentane (XIII) In 10 ml. of benzene is dissolved 550 mg. of la-acetoxy- 25 methoxycarbonyl 3oz (6 ethoxycarbonylhexyl)- 4a-carboxycyclopentane and to the solution is added 3 ml. of oxalyl chloride. The mixture is refluxed for 3 hours and, after addition of 5 ml. of oxalyl chloride, left to stand overnight at room temperature. After completion of the reaction, the solvent and an excess of the reagent are distilled off from the reaction mixture to give the desired product as oil. The product thus obtained may be employed without purification in the next reaction.

PREPARATION 10 1wacetoxy-Zfi-methoxycarbonyl-3a-( 6-ethoxycarbonylhexyl) 4a-acetylcyclopentane (XIV) To a dimethyl cuprous lithium ether solution prepared by adding 13.24 ml. of a 0.8 M solution of methyl lithium in ether to a solution of 1.018 g. of cuprous iodide in 15 ml. of ether, is added dropwise at 78" C. a solution of the 1a-acetoxy-ZB-methoxycarbonyl-3a-(6-ethoxycarbonylhexyl)-4a-chlorocarbonylcyclopentane obtained in Preparation l0 dissolved in 5 ml. of ether. After completion of the addition, the reaction mixture is left to stand for 20 minutes, diluted with 5 ml. of methanol at 78 C. and neutralized by addition of aqueous acetic acid. The mixture is extracted with ether at 0 C. The extract is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residues are subjected to column chromatography using 10 g. of silica gel and eluted with some amount of benzene and next successively with a benzene solution containing 1-5% ether. The eluates with the benzene solution containing 1-5% ether 15 are collected and the solvent is distilled off -to give 330 mg. of the desired product as oil.

LR. (liquid film) v cmf N.M.R. (CDCl :p.p.m.

4.74 (1H, multiplet PREPARATION 11 1a,4u-diacetoxy-2fl-methoxycarbonyl-3 a- 6-ethoxycarbonylhexyl cyclopentane (XV) To a solution of 309 mg. of 1a-acetoxy-2/i-methylcarbonyl 3oz (6 ethoxycarbonylhexyl) 4oz acetylcyclopentane and 1.85 g. of disodium hydrogenphosphate in 5 ml. of methylene chloride is added dropwise under icecooling a methylene chloride solution of pertrifluoroacetic acid prepared by 0.135 ml. of 90% hydrogen peroxide, 3 ml. of methylene chloride and 0.85 ml. of anhydrous trifluoroacetic acid. After completion of the addition, the mixture is stirred at room temperature for 45 minutes. After completion of the reaction, the reaction mixture is diluted with water and extracted with ether. The extract is washed successively with water, aqueous sodium iodide, aqueous sodium thiosulfate and water and dried over anhydrous sodium sulfate. The solvent is distilled olf to give 312 mg. of the desired product as oil.

I.R. (liquid film) v cmr z 4.70 (2H, multiplet,

oooon. H

ooocri. H

5.80 (2H, quartette, CH CH OCO) 6.22 3H, singlet, CH OCO-) 7.89 (3H, singlet, CH COO--) 7.91 (3H, singlet, CH COO) 8.69 (3H, singlet, CH CH OCO') PREPARATION l2 1a ,4ct-dihydroxy-2fl-methoxycarbonyl-3u-(6-ethoxycarbonylhexyl)cyclopentane (XVI) To a solution of 4.151 g. of 1u,4a-diacetoxy-2,8-methoxy-carbonyl-3u-(6-ethoxycarbonylhexyl)cyclopentane in 100 ml. of absolute ethanol is added 7.5 g. of potassium carbonate and the mixture is stirred at 45 C. for one hour. After completion of the reaction, acetic acid is added to the reaction mixture and the solvent is distilled 011?. The residues are extracted With ether and the solvent is distilled oif from the extract. The residues are subjected to column chromatography using 35 g. of silica gel and eluted with successively some amount of benzene-a benzene solution containing 18% ether and next successively with a benzene solution containing 20-30% ether. The eluates with the benzene solution containing 2030% ether are 16 collected and the solvent is distilled oif to give 1.264 g. of the desired product as oil.

I.R. (liquid film) v cmf z N.M.R. (CDCl 1-:p.p.m. 5.70 (2H, broad singlet,

5.80 (2H, quartette, CH CH OCO--) 6.30 (3H, singlet, CH OCO) 8.70 (3H, triplet, CH CH CO) PREPARATION 13 1u,4a-di Z-tetrahydropyranyloxy -2/8-methoxycarb0nyl- 3 u-( 6-ethoxycarbonylhexyl) cyclopentane (XVII) In 6 ml. of benzene is dissolved 1.429 g. of 1a,4oz-dihydroxy 2p methoxycarbonyl 3a (6 ethoxycarbonylhexyl)cyclopentane and to the solution is added 5 ml. of dihydropyran and a small amount of picric acid. The mixture is left to stand for 11 hours under ice-cooling and and subsequently at ---15 C. overnight. After completion of the reaction the solvent is distilled off from the reaction mixture. The residues are subjected to column chromatography using 10 g. of neutral alumina (Grade III, Woelm Co.) and eluted with benzene. The eluates are collected and the solvent is distilled off to give 2.192 g. of the desired product as oil.

I.R. (liquid film) v cmr N.M.R. (CDCl -r:p.p.m. 5.45 (2H, broad singlet,

5.81 (2H, quartette, CH CH OCO) 6.31 and 6.32 (3H, CH OCO-) 8.1 (3H, triplet, CH CH OCO) PREPARATION 14 1 0:,4a-di Z-tetrahydropyranyloxy -2l3-hydroxymethyl- 3 a- (6-ethoxycarbon'ylhexyl cyclopentane (XIX) To a solution of 635 mg. of 111,40: di(2 tetrahydropyranyloxy) 213 methoxycarbonyl 3a (G-ethoxycarbonylhexyl)cyclopentane in 10 ml. of absolute ethanol is added 1.2 g. of sodium boron hydride and the mixture is stirred at 0 C. for 25 hours. After completion of the reaction, a small amount of acetic acid is added to the reaction mixture is order to decompose the excess of sodium boron hydride. The mixture is diluted with water and extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled oil? from the extract. The residues are subjected to column chromatography using 2 g. of neutral alumina (Grade 111, Woelm Co.) and eluted successively with some amount of hexane-'a hexane solution containing benzene and next successively with a hexane solution containing 40-60% benzene. The eluates with the hexane solution containing 40-60% benzene are collected and the solvent is distilled oil to give mg. of the starting material. The elution is continued using successively benzene--a benzene solution containing 30% ethyl acetate to give 149 mg. of the desired product as oil.

LR. (liquid film) v cmr N.M.R. (CDCl r:p.p.m. 5.30 (2H, broad singlet,

5.80 (2H, quartette, CH CH OCO) 8.1 (3H, triplet, CH CH OCO-) PREPARATION 15 10:,4a-di (Z-tetrahydropyranyloxy) -2 3-methoxycarbonyl- 3 a- (6-carboxyh exyl cyclopentane (XVIII) In 70 ml. of 30% aqueous methanol containing potassium carbonate is dissolved 3 g. of 1a,4u di(2-tetrahydropyranyloxy) 218 methoxycarbonyl 3a (6 ethoxycarbonylhexyl)cyclopentane and the solution is stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture is diluted with water and hexane is added to the mixture. The hexane layer is separated and washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 1.521 g. of the starting material. The aqueous layer is made acidic by addition of acetic acid and extracted with ethyl acetate. The extract is washed with water and dried. The solvent is distilled 01f to give 1.432 g. of the desired product as oil.

LR. (liquid film) u cmr z N.M.R. (CDCl 'r:p.p.m.

5.30 (2H, broad singlet 6.32 (3H, singlet, CH OCO-) PREPARATION 16 1a,4a-di 2-tetrahydropyranyloxy) -2;3-hydroxymethyl- 3ot(6carboxyhexyl cyclopentane (XIX) In 100 ml. of anhydrous tetrahydrofuran is dissolved the potassium salt prepared from 1.4 g. of 111,40; di(2- tetrahydropyranyloxy) 2B methoxycarbonyl 3oz (6- carboxyhexyl)cyclopentane and 330 mg. of potassium bicarbonate and, after addition of 1.4 g. of lithium boron hydride, the mixture is refluxed for 15 hours. After completion of the reaction, ice water and subsequently a small amount of dilute hydrochloric acid are added to the reaction mixture to decompose the excess of lithium boron hydride. The mixture is extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residues are subjected to column chromatography using 7 g. of silica gel and eluted some amount of hexane and next successively with benzene-a benzene solution contained 30% ethyl acetate. The eluates with the benzene solution containing 30% ethyl acetate are collected and the solvent is distilled off to give 995 mg. of the desired product as oil.

LR. (liquid film) v cmr 1700, 3300-3400. N.M.R. (CDCl -r:p.p.m.

5.30 (2H, broad singlet,

18 PREPARATION 17 111,40; di(2 tetrahydropyranyloxy)-2p-formyl-3a-(6- ethoxycarbonylhexyl)cyclopentane (XX) To a solution of 1a,4a di(2 tetrahydropyranyloxy)- 2 8 hydroxymethyl 3a (6 ethoxycarbonylhexyl)cyclopentane in 25 ml. of methylene chloride is added 2.5 g. of anhydrous chromic acid-pyridine complex under icecooling and the mixture is stirred for 15 minutes. After completion of the reaction, the reaction mixture is extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 123 mg. of the desired product as oil.

I.R. (liquid film) v cmr' z The absorption caused by the hydroxy group was not observed.

PREPARATION 18 Preparation of prostaglandin Fla from 111,411 di(2-tetrahydropyranyloxy) 2p formyl 3a (6-ethoxycarbonylhexyl)cyclopentane (XX) 9a,l1a,15a trihydroxyprost 13 (trans) epoic acid (prostaglandin F (1) To a solution of 123 mg. of 10:,411 di(2 tetrahydropyranyloxy) 2/3 formyl 3a (6 ethoxycarbonylhexyl)cyclopentane in 5 ml. of ether is added a solution of 168 mg. of tri n butylphosphin 2 oxoheptylide in 1.5 ml. of ether and the mixture is stirred at room temperature for 17 hours. After completion of the reaction, the solvent is distilled oil from the reaction mixture. The residues are subjected to column chromatography using 3 g. of neutral alumina (Grade 111, Woelm Co.) and eluted successively with some amount of hexanea hexane solution containing 8% benzene and next with a hexane solution containing 10% benzene. The eluates with the latter solvent are collected and the solvent is distilled off to give oils. The oils are further subjected to column chromatography using 3 g. of silica gel and eluted with some amount of benzene and next successively with a benzene solution containing 1-5% ether. The eluates with the henzene solution containing 15% ether are collected and the solvent is distilled off to give 138 mg. of ethyl 9a,11ot di(2 tetrahydropyranyloxy) 15 oxoprost-13(trans)- enoate.

LR. (liquid film) v cmr z N.M.R. (CDCl -r:p.p.m.

2.8-4.2 (2H, multiplet,

5.39 (2H, broad, singlet,

(2) To a solution of 270 mg. of ethyl 9oz,11oz-di(2- tetrahydropyranyloxy) 15 oxoprost 13(trans)-enoate in 20 ml. of methanol is added 500 mg. of sodium boron hydride under ice-cooling and the mixture is stirred at 0 C. for one hour. After completion of the reaction, ice Water and subsequently acetic acid are added to the reaction mixture to decompose the excess of sodium boron hydride. The mixture is extracted with ether and the extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off from the extract.

5.80 (2H, quartette, CH CH OCO-) 5.90 (2H, broad singlet,

The residues are subjected to column chromatography using 4.5 g. of silica gel and eluted successively with some amount of benzene-a benzene solution containing 3% ether and next successively with a benzene solution containing 5% etherethyl ether. The eluates with the ben- 5 zene solution containing 5% ether-ethyl acetate are collected and the solvent is distilled oil to give 144 mg. of ethyl 9a,11u-di(Z-tetrahydropyranyloxy) 15 hydroxyprost-13 (trans) -enoate.

no H

LR. (liquid film) v cmr z 10 970 (trans double bond), 3470. 3.73 (3H, triplet, CH CH OCO) (CDC13) F Mass spectrum M -H Oz 352.

4.40 (2H, multlplet,

15 (4) In 5 ml. of 30% aqueous methanol containing 2% potassium hydroxide is dissolved 60 mg. of ethyl 90a, 11a, l5a-trihydroxyprost-l3(trans)-enoate and the solution is stirred at room temperature and subsequently at 50 C. for 3 hours. After completion of the reaction, a small amount of acetic acid is added to the reaction mixture and the solvent is distilled off under reduced pressure. The residues are dissolved in ethyl acetate-ether (1:1) and washed with a small amount of water and the solvent is distilled off. To the residues is added an ether-hexane solution to crystallize. The crude crystals are recrystallized from ethylacetate-hexane to give 23 mg. of pure 9a,lla, l5a-trihydroxyprost-13(trans)-onoic acid (prostaglandin Fla) melting at 78-79.5 C.

I.R. (melt) v 2 960 (trans double bond), 1710, 3350.

N.M.R. (CDCl r:p.p.m. 4.55 (2H, multiplet,

(3) In a mixture of 1 m1. of tetrahydrofuran, 10 ml. of acetic acid and 5 ml. of water is dissolved 124 mg. of ethyl 941,110: di(2 tetrahydropyranyloxy)-1S-hydroxyprost -13 (trans) enoate and the solution is stirred at 30-40 C. for 2 hours. After completion of the reaction, the reaction mixture is diluted with water and extracted with ethyl acetate-ether (1:1). The extract is Washed with water and dried over anhydrous sodium sulfate and the solvent is distilled 01f to give 110 mg. of oils. The oils are subjected to column chromatography using 2 g. of silica gel and eluted successively with some amount of benzene-a benzene solution of 10% ethyl acetate and next successively with a benzene solution containing -30% ethyl acetate. The eluates with the benzene solution containing 20-30% ethyl acetate are collected and the solution is distilled oif to give 20 mg. of ethyl 9a,11a,15/3-trihydroxyprost 13 (trans) enoate as oil. The elution is continued using successively a benzene solution containing 30-40% ethyl acetate to give 50 mg. of a mixture of ethyl 9a,1la,15p-trihydroxyprost 13 (trans)-enoate and ethyl 9a,l1a,15oc trihydroxyprost 13 (trans) enoate as oil.

6.00 (3H, broad, singlet,

The elution is further continued using successively a ben- Ito H zene solution containing 60-80% ethyl acetate to give 28 mg. of ethyl 9a,11ot,l5ot trihydroxyprost 13 (trans)- enoate as oil.

Ethyl 9a,11u,1SB-trihydroxyprost-13-(trans)-enoate. Ho H 110' H I.R. (CHCl v cmfh 970 (trans double bond), 1730, 3400. N.M.R. (CDCl T:p.p.m.

4.42 (2H, multiplet,

Mass spectrum MH O: 338.

Example H 1a-hydroxy-2 3-methoxycarbonyl-3a(6-ethoxycarbonyl- H hexyl)-4u-carboxycyclopentane (I) b d 1 In a mixture of 30 ml. of ethanol and 7.5 ml. of water (2H, ma 5mg at, .55 is dissolved 1.221 g. of 2-fl-methoxycarbonyl-3a-(6-ethoxycarbonylhexyl) -4a-carboxycyclopentanone and to the 0 H solution is added 880 mg. of sodium bicarbonate. To the mixture is added 400 mg. of sodium boron hydride under ice-cooling and the mixture is left to stand for 15 minutes.

After completion of the reaction, Water and subsequently H 6- H a small amount of acetic acid are added to the reaction 5.81 (2H, quartette, CH CH OCO) 8.73 (3H, triplet, CH CH OCO) Ethyl 9a,11a,15a-trihydroxyprost-13-(trans)-enoate.

LR. (CHCl v cmr' 970 (trans double bond), 1730, 3400.

mixture in order to decompose the excess sodium boron hydride. The mixture is made acidic by addition of concentrated hydrochloric acid and extracted with ether. The extract is washed with water and dried over anhydrous sulfuric acid. The solvent is distilled oil. The residues thus obtained are subjected to column chromatography using 12 g. of silica gel washed with an acid and eluted with some amount of benzene and next successively with a benzene solution contain 10-20% ether. The eluates with the benzene solution containing 1020% ether are collected and the solvent is distilled off to give 730 mg. of the desired product as oil.

I.R. (liquid film) v cmr' z 1715, 1742, 3250, 3480.

21 N.M.R. (CDCI 1-:p.p.m.

3.28 (2H, broad singlet, COOH and --OH) 5.58 (1H, singlet,

UCOOR wherein R and R may be the same or different and each represents an alkyl group having 1-6 carbon atoms or its optical isomer or the racemic mixture thereof.

2. 1a hydroxy 2/8 methoxycarbonyl-3a-(6-ethoxy- 25 carbonylhexyl)-4a-carboxycyclopentane.

22 3. A compound having the formula goon ' ---(CH;)6CO0R 1-00 0R wherein R and R may be the same or different and each represents an alkyl group have 1-6 carbon groups, or its optical isomer or the racemic mixture thereof.

4. A compound of claim 3 comprising ZB-methoxycarbonyl 3a (6 ethoxycarbonylhexyl)-4a-carboxycyclo pentanone.

References Cited House, Modern Synthetic Reactions, pp. 23-31 (1965). Katsube et al., Asi. Biol. Chem., 35, 1828 (1971).

ROBERT GERSTL Primary Examiner US. Cl. X.R.

260345.7, 345.8, 345.9, 347.5, 404, 410 R, 413, 464, 465 D, 468 D, 476 R, 483, 488 R, 514 D, 557 R I UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 806.535 f Dated Aprilfl23, 1974 Inventor(s) KIYOSHI SAKAI et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line '50: replace with Column 2, line 28: I delete "2formylcyclopentane derivatives I having the formula" Column 8, line 23: replace "perluric" with perlauric--- Column 9, line 36: after "sodium bicarbonate", insert a comma Column 11, lines 29-41: rewrite as follows:

--4.80. (2H, singlet, @C IEQOCO- 5.83 (2H, quartette, cH cg oco- 6.51 (2H, singlet, cr1 ococg co- 8.75 (3H, triplet, c cH oco- Column 12, I lines 6-12: rewrite as follows:

. --2;64 (5H, singlet, C fi 4.83. (2H, singlet, C H C OC0 FORM l e-1050 (IO-69) V USCOMM-DC scan-P09 l-LS. GOVEWNMI!" I'Il'fl'lnfi O FICE: Hi9 0-355-334.

UNl ED STATES PATENT OFFICE PAGE 2 CERTIFICATE OF CORRECTION Patent No. 3,806,535 Dated April 23, 1974 Inventor(s) KIYOSHI SAKAI et al It is certified that error appears in the aboveiden'tified patent and that said Letters Patent are hereby corrected as shown below:

5.88 (23, qua-rtette, crl c oco- 6.32 (B l 1, singlet, CAI3OCO 6.70 (3H; singlet, CE3O- 8.76 (5H, triplet, c l cll oco- Column 12, lines 1.8-25: I rewrite as follows:

---2'.67 (5H, singlet, 0 5

4.82 (2H, singlet, c H C Oc0- 4.95 -(lH, singlet, CH OCOC I=( ZCH I OCH3 5.89 (2H, quartette, CH C OCO- .PAGE 3 UNITED STATES PATENT OFFICE.

CERTIFICATE OF CORRECTIGN Patent No. 3,806,535 Dated April 23, 1974 Inventor-(s) 'KIYOSH'I SAKAI et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

6.{30-.(3H, singlet, CI-3OCO 8,7 8 (3s,- triplet, cg cH oco- Colurr m 13, lines 13-24: rewrite as follows:

J 1 v 4.80 (2H, @cgpco- 5.87 (2H, cn cg ocol 6. 16 (in, cg oco- 8.75 (23H, cg cn oco- Column 13, lines 72-75: rewrite as followsi -2.06 (1H, singlet, 40% I 5.88 (2H, quartette, CH C Ii OCO 6.23 'V(3H, singlet, c I3 oco- 8.74 (3H, triplet, cg cH oco- Column 14, linesi'24-4O: rewrite as follows:

--l.48 (1H, broad singlet, -COO DRM PO-IOSO (IO-59) uscoMM-oc scan-pea n u.s. covznun uar "nu-mo omc: I n a PAGE 4 UNITED STATES PATENT OFFICE CE-RTIFICA'IE 0F CORRECTION Patent No. 3,806,535 Dated April 23, 1974 Inventor(s) KIYOSHI SAKAI et al It is certified that error appears in the above-identified patent arTrI that said Letters Patent are hereby corrected as shown below:

0... a 4.7l (1H, multiplet,

I i 0 iv OCOCH3 5. 85 (2H, quartette, CH3C2OCC 6.27. Y(3H, singlet, cg oco- 7.95, 3 singlet, cg c oo- 8.73 (311, triplet, cg cH oco- Column 15, lines 6-20: rewrite as follows:

.4,.7 L (lH, multiplet H 5.86 (2H, quartette, cH c 0co- 5.30 (3H, singlet, cg oc o- 7.85 (3H, singlet, C3CO 7.95 (3li, singlet, c coo- 8.56 (:3H, triplet, c cH 0coi Column 15, lines 44-57: rewrite as follows:

F OR-d PO-! 050 (10-69) USCOMM-DC 80376-1 59 I .5. GOVEIN'OiNY PIINYING OFFICE I95 9-3533L PAGE 5 UNITED STATES PATENT OFFICE "CERTIFICATE OF CORRECTION i Patent No.- 3,806,535 3 Dated A ril 23, 1974 Inventor-(s) KIYOSHI SAKAI .et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

QQQ -4.70 (2H, multiplet,

If We 0602:111

5.80 (2H, quartette, CH CI OCO 6.22 (3H, singlet, .C H OCO 7.89 (3H, singlet, cg coo- 7.91 (3H, singlet, C I;I CO0 8.69 (3H, singlet, CI CH OCO Column 16, lines 63-20: rewrite as follows:

. g 3 OH v ---5.70 (2H, broad singlet,

5.80 (2H, quartette, C CH OCO 6.30 (3H, singlet, C OCO- 8.70 (3H, triplet, cg cn co- Column 16, lines 41-52: rewrite as follows:

- CERTIFICATE OF CORRECTION Patent No. 3,806,535 Dated Agril 23,1974

Inventor(s) KIYOSHI SAKAI et el It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

, Column 17, lines 6-14: rewrite as follows:

---5.30 (2H, broad singlet,

' I 5.80 (2H, quartette, cH c rg oco- 8.71 (3H, tri 1et, cg cH' oco Column 17, lines 36-43: rewrite as follows:

-5.30 (2H, broad singlet 0 6.32 3H, singlet, C E OCO (lolumn 17, lines 70-75: rewrite as follows:

-5.30 (2H, broad singlet, ll

ORM PC4050 (IO-69) uscoMM-oc man-ps9 0.5. GOVERNMENT PI IOUHG OFHC! I96! 0-156-336.

PAGE 7 NITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,806,535 Dated April 23, 1.974

Inventor(s) KIYOSHI SAKAI et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 18, lines 50-65: rewrite as follows --2.8-4.2 (2H, multiplet,

5.39 I (2H, broad, singlet,

Column 19, lines 13-18; rewrite as follows:

. QI-IIV --4.40 (2H, multlplet,

7 Column 19, lines 48-65: rewrite as follows:

-4.42 (2H, 'multiplet,

HO WW 5.80 (2H, broad singlet,

5.81 (2H, quartette, cH cg 0co- 8.73 '(BH, triplet, C'EI3CHZOCQ- Column 19, line 72 Column 20, line 12: rewrite as follows:

. 4 58 (2H, multiplet PAGE'B UNITED STATES PATENT. OFFICE CERTIFICATE OF CORRECTION Patent No. 3,8064535 Dated" Agril 23, 1974- Inventor(s) KIYOSHI SAKAI et al It is certified; that; error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

5.80 (2 iqu arte tce, oH c5 oco- 13 5.90 (2H, :broad singlet,

- 2 HO 8.73 (3H, trlplet, C I CH OCO e M Column 20, lines 32-45! rewrite as follows:

--4.55 (2H, multiplet,

. HO Column 21, lines 2-10; rewrite as follows: w

-3.28 (2H, broad singlet, -C(3O I, am? -0 5.58 (1H, singlet, Q

5.85 (2H, quartetc e, CH C E I OCO Column 22, line 11: replace "have" with --having--- Signed and sealed this 21st day of, Janualy 1975.

(SEAL) Attest:

McCOY GIBSQN JR. C. MARSHALL DANN Attestlng Off1cer v Commissioner of Patents FORM PO-IOSO (10-69) USCOMM DC Goa-W'Psg u.s. GOVERNMENT rnmnm; a ncc; l9! O-Jii-Jl.